Various vaccine vectors or adjuvants that induce potent T cell responses are known in the art (Kaufmann and Hess, 1997). However, very few vaccine vectors exist that induce rapid and potent memory CD8+ cytolytic T cell responses, and that are safe and cost-effective (Raupach and Kaufmann, 2001). Unlike other T cells, CD8+ T cells uniquely provide immune-surveillance to the entire body because they recognize targets in the context of MHC class I molecules, which are present in every cell (Bevan, 1995). Furthermore, CD8+ T cells can eliminate infected cells or tumour cells rapidly. Thus, the induction of specific, potent CD8+ T cells is highly desirable for diseases that are caused by intracellular pathogens and tumours.
Intracellular pathogens induce CD8+ T cell responses; however, the responses are either highly attenuated or the organism itself is highly toxic. Generally, rapid proliferation of pathogens is countered by rapid presentation of antigen to CD8+ T cells within the first few days of infection and activated CD8+ T cells undergo profound expansion (>1000-fold) within the first week of infection, which results in resolution of infection (Kaech and Ahmed, 2001). Similarly, CD8+ T cells play a key role in mediating immune-surveillance against tumours (Smyth et al., 2000). While antibodies and helper T cells mainly promote clearance of extracelluar pathogens (Kaech et al., 2002), CD8+ T cells play a principal role in controlling intracellular pathogens and tumours. Thus, rapid induction of memory CD8+ T cells is essential for developing vaccines against tumours or intracellular pathogens.
While the CD8+ T cells play a key role against various diseases, their induction is highly tedious. Antigenic proteins injected into hosts in the absence or presence of adjuvants does not lead to the induction of CD8+ T cells (Moore et al., 1988). This is mainly because extracelluar proteins do not gain access to the cytoplasm (cytosol) of antigen-presenting cells (APC) (Rock, 1996). Rather, these extracellular proteins or vaccines are trafficked through specialized intracellular vesicles called phagosomes, which leads to the activation of helper T cells to aid antibody production. For induction of CD8+ T cell responses, the pathogen or the vaccine has to reside within the cytosol of an antigen-presenting cell (Bahjat et al., 2006).
Alternative routes of cross-presentation of non-cytosolic antigens to T cells have been suggested (Schaible et al., 2003; Houde et al., 2003; Yrlid and Wick, 2000), however the efficiency of these pathways in controlling pathogens isn't clear (Freigang et al., 2003). Dendritic cells may pick up antigen from dying APCs and present it to CD8+ T cells (Albert et al., 1998). Salmonella enterica serovar Typhimurium (ST) induces rapid death of macrophages and dendritic cells (Hersh et al., 1999; van der Velden et al., 2000) and it has been shown that cross-presentation of ST antigens occurs through dendritic cells (Yrlid and Wick, 2000). Phagosomes have themselves been considered to be competent at promoting cross-presentation (Houde et al., 2003). However, these mechanisms are of little protective value since rapid pathogen elimination is not observed. Cells that are cross-presenting ST antigens don't appear to serve as good targets for CD8+ T cells to mediate their function. Thus, target cell accessibility seems to be the critical difference between direct and cross-presentation.
Subunit vaccines that consist of purified proteins admixed with adjuvants typically do not induce CD8+ T cell response due to residence of these entities within phagosomes of cells (Bahjat et al., 2006). However, some adjuvants induce CD8+ T cell responses most likely by the cross-presentation pathway (Krishnan et al., 2000). Subunit vaccines are difficult to mass-produce and are faced with numerous technical difficulties including batch to batch variability, quantitation of the antigen-adjuvant ratio, and extensively laborious procedures. To avoid this problem, live vaccines are preferred. However, live vaccines can be either over- or under-attenuated and it is difficult to find the right balance (Raupach and Kaufmann, 2001).
Typically, viral infections (such as Lyphochoriomeningitis virus, LCMV) lead to potent activation of CD8+ T cell responses due to their replication within the cytosol of infected cells (Kaech et al., 2002; Murali-Krishna et al., 1998). However, it is difficult to justify the use of viral vectors as a live vaccine due to the lack of availability of reagents to control the virus, particularly in immunocompromised hosts. Live bacteria can be considered as an alternative option for vaccine development since antibiotics can be used in case they are not controlled by the host. However, extracellular bacteria do not gain access to the cytosol of infected cells, hence fail to induce CD8+ T cell response (Bevan, 1995). On the other hand, intracellular bacteria induce CD8+ T cell response, albeit poor, despite residing within the phagosomes of infected cells, perhaps by cross-presentation (Kaufmann, 1993)—the caveat being that intracellular bacteria (e.g., Salmonella, Mycobacteria, Leishmania) that reside within the phagosomes of infected cells induce a chronic infection, implying that CD8+ T cells fail to eradicate them from the host (Kaufmann, 1993; Hess and Kaufmann, 1993).
There remains a need in the art for a safe, cost-effective method to induce rapid and potent memory CD8+ cytolytic T cell responses.